CD8-Targeted PET Imaging of Tumor-Infiltrating T Cells in Patients with Cancer: A Phase I First-in-Humans Study of 89Zr-Df-IAB22M2C, a Radiolabeled Anti-CD8 Minibody

Abstract

There is a need for in vivo diagnostic imaging probes that can noninvasively measure tumor-infiltrating CD8+ leukocytes. Such imaging probes could be used to predict early response to cancer immunotherapy, help select effective single or combination immunotherapies, and facilitate the development of new immunotherapies or immunotherapy combinations. This study was designed to optimize conditions for performing CD8 PET imaging with ⁸⁹Zr-Df-IAB22M2C and determine whether CD8 PET imaging could provide a safe and effective noninvasive method of visualizing the whole-body biodistribution of CD8+ leukocytes. Methods: We conducted a phase 1 first-in-humans PET imaging study using an anti-CD8 radiolabeled minibody, ⁸⁹Zr-Df-IAB22M2C, to detect whole-body and tumor CD8+ leukocyte distribution in patients with metastatic solid tumors. Patients received 111 MBq of ⁸⁹Zr-Df-IAB22M2C followed by serial PET scanning over 5-7 d. A 2-stage design included a dose-escalation phase and a dose-expansion phase. Biodistribution, radiation dosimetry, and semiquantitative evaluation of ⁸⁹Zr-Df-IAB22M2C uptake were performed in all patients. Results: Fifteen subjects with metastatic melanoma, non-small cell lung cancer, and hepatocellular carcinoma were enrolled. No drug-related adverse events or abnormal laboratory results were noted except for a transient increase in antidrug antibodies in 1 subject. ⁸⁹Zr-Df-IAB22M2C accumulated in tumors and CD8-rich tissues (e.g., spleen, bone marrow, nodes), with maximum uptake at 24-48 h after injection and low background activity in CD8-poor tissues (e.g., muscle and lung). Radiotracer uptake in tumors was noted in 10 of 15 subjects, including 7 of 8 subjects on immunotherapy, 1 of 2 subjects on targeted therapy, and 2 of 5 treatment-naïve subjects. In 3 patients with advanced melanoma or hepatocellular carcinoma on immunotherapy, posttreatment CD8 PET/CT scans demonstrated increased ⁸⁹Zr-Df-IAB22M2C uptake in tumor lesions, which correlated with response. Conclusion: CD8 PET imaging with ⁸⁹Zr-Df-IAB22M2C is safe and has the potential to visualize the whole-body biodistribution of CD8+ leukocytes in tumors and reference tissues, and may predict early response to immunotherapy.

Trial registration: ClinicalTrials.gov NCT03107663.

Keywords: 89Zr-Df-IAB22M2C; CD8+ T cell; PET imaging; immunotherapy; minibody.

Graphical abstract

FIGURE 1.

Serum clearance and biodistribution of ⁸⁹Zr-Df-IAB22M2C. (A) Serum clearance of ⁸⁹Zr-Df-IAB22M2C based on enzyme-linked immunosorbent assay measurements (limit of detection = 5 ng/mL). No minibody was detected in serum at the 0.2-mg dose. (B) Whole-body PET images of a patient at various times after injection of ⁸⁹Zr-Df-IAB22M2C (1.5-mg minibody dose) demonstrating the distribution of ⁸⁹Zr-Df-IAB22M2C in normal tissues and uptake in a nodal metastasis in the right neck (arrow), with good visualization of uptake in the nodal metastasis at 24–48 h after injection.

FIGURE 2.

⁸⁹Zr-Df-IAB22M2C uptake in normal tissues and tumor lesions versus time. (A) ⁸⁹Zr-Df-IAB22M2C uptake in CD8-rich reference tissues in patients administered 0.5 and 1.5 mg of minibody mass. (B) ⁸⁹Zr-Df-IAB22M2C uptake in CD8-poor reference tissues in patients administered 0.5 and 1.5 mg of minibody mass. (C) Box and whisker plots of ⁸⁹Zr-Df-IAB22M2C uptake in tumor lesions from all subjects (n = 15). Boxes outline first and third quartile values. Median SUV_MAX values are indicated by horizontal line and mean SUV_MAX values are indicated with +. Outlier values are indicated by dots. (D) ⁸⁹Zr-Df-IAB22M2C mean tumor uptake in patients who received 0.5 and 1.5 mg of minibody mass. BM = bone marrow; LN = lymph nodes.

FIGURE 3.

A 77-y-old man with metastatic melanoma treated with pembrolizumab. CT and fused ¹⁸F-FDG PET/CT images (left) acquired at approximately 8 mo after initiation of immunotherapy demonstrate 2 ¹⁸F-FDG–avid nodal metastases in right neck (SUV_MAX = 8.0, top image; SUV_MAX = 16.8, bottom image), which could represent viable metastases. Corresponding CT and fused CD8 PET/CT images (right) obtained at 1 mo after ¹⁸F-FDG PET/CT demonstrate significant tracer activity in both metastases (SUV_MAX = 5.4, top image; SUV_MAX = 14.6, bottom image), which suggests that some of the ¹⁸F-FDG activity could be due to tumor-infiltrating CD8+ T cells rather than tumor cells. Follow-up imaging over the next 6 mo demonstrated stable disease, supportive of this hypothesis.

FIGURE 4.

A 71-y-old man with locally advanced stage III melanoma treated with pembrolizumab. Baseline CT and fused ¹⁸F-FDG PET/CT images (left) demonstrate 2 ¹⁸F-FDG–avid metastases in left axilla (SUV_MAX = 10.0, medial node; SUV_MAX = 7.6, lateral node). CT and fused CD8 PET/CT images (middle) obtained at 28 d after start of immunotherapy demonstrate increased tracer activity in both metastases (SUV_MAX = 9.5, medial node; SUV_MAX = 10.0, lateral node), suggestive of tumor infiltration by CD8+ T cells. Follow-up imaging with contrast-enhanced CT (right) demonstrated complete response to therapy.